Prostaglandin endoperoxide synthetase-dependent cooxidation of acetaminophen to intermediates which covalently bind in vitro to rabbit renal medullary microsomes.
The metabolism of acetaminophen during prostaglandin biosynthesis was studied in vitro. [3H]Acetaminophen was rapidly metabolized by ram seminal vesicle microsomes to an intermediate(s) which covalently binds to microsomal protein. Arachidonic acid, a substrate for the fatty acid cyclooxygenase component of prostaglandin endoperoxide synthetase (PES), was required to support binding. The cyclooxygenase inhibitor indomethacin inhibited binding. Cumene hydroperoxide, a substrate for the hydroperoxidase component of PES, supported covalent binding which was not inhibitable by indomethacin. Acetaminophen also stimulated oxygen uptake during prostaglandin biosynthesis in a dose-dependent manner. By using a purified PES preparation with bovine serum albumin as the acceptor protein, similar results were obtained. Binding was dependent upon the presence of PES and arachidonic acid and was inhibited by indomethacin. Experiments were then carried out by using microsomes prepared form the rabbit kidney medulla, a possible target organ of acetaminophen-induced toxicity. Arachidonic acid and cumene hydroperoxide supported covalent binding, whereas indomethacin inhibited binding supported by the former but not the latter. Reduced glutathione prevented covalent binding to protein when added to the incubation mixture and NADPH did not support binding. The results suggest that the cooxidation of acetaminophen during prostaglandin biosynthesis may play a role in the renal metabolism and possible nephrotoxicity of this compound.
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001555:Benzene Derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D010084:Oxidation-Reduction; D010545:Peroxides / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits; D012669:Seminal Vesicles / Q000378:metabolism; D012756:Sheep
D001095:Arachidonic Acids; D001555:Benzene Derivatives; D010545:Peroxides; D016718:Arachidonic Acid; D000082:Acetaminophen; D011451:Prostaglandin-Endoperoxide Synthases; C007164:cumene hydroperoxide